There have been known a great number of optically active natural or unnatural amino acid derivatives which are useful as intermediates of drugs and pesticides, physiologically active substances, etc. It is still an important problem to develop an efficient process for producing these derivatives. As noteworthy processes, there have been reported several processes of activating the OH-group at the β-position of optically active serine and then reacting with a nucleophile or an electrophile.
Examples of these processes are as follows:
(1) a process wherein an optically active N-tosyl-aziridine-2-carboxylic acid derivative is reacted with lithium acetylide of trimethylsilyl acetylene (Tetrahedron Lett. vol. 36, 151 (1995));
(2) a process wherein an optically active N-protected-3-iodo-alanyl ester is substituted at the 3-position by reacting with a nucleophile (Tetrahedron, vol. 41, 1833 (1985));
(3) a process wherein an optically active N-protected-3-iodo-alanyl ester is converted into an organic zinc compound and then reacted with an electrophile (J.O.C., vol. 57, 3397 (1992));
(4) a process wherein a β-lactam derivative or a sulfamidate derivative is produced from a serine derivative and then reacted with a nucleophile (J. Am. Chem. Soc., vol. 107, 7105 (1985)); and
(5) a process wherein an optically active N-protected-aziridine-2-carboxylic acid ester is synthesized from a serine derivative and then reacted with an organic copper reagent (JP-A-7-252202; the term “JP-A” as used herein means an “unexamined published Japanese patent application”), etc.
In addition, there has been known a process for producing aziridine-2-carboxylic acid by treating a 3-haloalanine or its ester or a mineral acid salt thereof with an alkali metal or alkaline earth metal hydroxide or aqueous ammonia in water or an aqueous organic solvent (JP-B-60-39357; the term “JP-B” as used herein means an “examined Japanese patent publication”).
Among the processes of activating the OH-group at the β-position of optically active serine and then reacting with a nucleophile or an electrophile, the above-described process (1) is not industrially advantageous. This is because the metal acetylide reagent should be used in large excess and only a poor yield can be achieved thereby. Moreover, it is needed in this process to synthesize the substrate in plural steps, which makes the performance troublesome.
Similarly, it is also needed to synthesize the substrate in plural steps in the processes (2) to (5), which makes the performance troublesome. To maintain the optical purity of a product at a high level, it is further needed to carry out the reaction at a low temperature with the use of a less basic organic copper reagent as the nucleophile and the occurrence of partial racemization is yet unavoidable. In these processes, furthermore, only an insufficient selectivity of functional groups is achieved and thus by-products having reacted with ester group are also formed.
As discussed above, these known processes each suffers from problems to be solved as an industrial process for producing optically active natural or unnatural amino acid derivatives. Therefore, it has been required to develop an industrially applicable process for producing optically active natural or unnatural amino acid derivatives without resort to any expensive reagents or troublesome procedures.
Concerning the process for producing aziridine-2-carboxylic acid as described above, the procedures and analytical methods are described in the document as cited above. When the inventors carried out a detailed follow-up experiment after establishing an appropriate analytical method, the yield reported in the document could be hardly achieved. It has been thus revealed that there is a serious problem in efficiently producing aziridine-2-carboxylic acid by this process on an industrial scale.